Alzheimer's disease (AD) is defined neuropathologically by extracellular plaques composed of ??amyloid (A?42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule?associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose to further optimize a unique set of small molecule drugs known as soluble gamma?secretase modulators (SGSMs) to further explore novel AD therapeutics. This proposal will focus on the medicinal chemistry lead optimization and the testing of the efficacy of these drugs aimed at halting A?42?related pathologies in AD transgenic mice. Our overarching hypothesis is SGSM therapy aimed to disrupt production of A?42 will be an efficacious treatment approach for prodromal or early AD as well as sporadic late?onset AD. The goal of this project is to complete all of the necessary IND-enabling studies and to file an IND on a very potent and safe SGSM.